Microbes started to be identified and associated with certain diseases, but it then took several decades before scientists started to glean answers about the identity of pathogenic microorganisms in comparison to their nonpathogenic counterparts, the nature of virulence traits, and the host response-quickly termed immunity. Genetics—more precisely, molecular genetics—was key to this understanding. The saga started with a bacterial pathogen. Recent genomic data on the causative microorganisms have illuminated some key aspects of their pathogenesis, particularly the correlation between genome reduction and obligate intracellular parasitism in Mycobacterium leprae. Regarding gene destruction, Shigella is characterized by a large number of pseudogenes, in comparison to Escherichia coli K-12, caused either by frameshift point mutations, deletions, or integration of insertion sequences which are present in very large numbers in the Shigella genome, compared to E. coli K-12. Moreover, further analysis indicated that when different Shigella and EIEC strains were compared, different types of deletions were accordingly observed. Elaborate enzymatic activities such as deubiquitinases and phos-pho-threonine lyases, an original family of E3 ligases, have been identified in both animal and plant pathogens. However, it remains a mystery in which original species (eubacteria, archaea, or primitive eukarya like protozoans) the core of genes that led to the diversification of the current pool of type III secretion system of Shigella(TTSS) effectors originally appeared. In the words of François Jacob, TTSS is a natural selection that gives direction to changes, orients chance, and slowly, progressively produces more complex structures, new organs, and new species.